Many allergic reactions involve the interaction of an antigen, also known as an allergen, with an antigen-specific-IgE antibody, also known as an allergen-specific-IgE antibody, and the consequent sequence of events. For a patient to be definitively diagnosed with a particular allergy, two expectations must be met.
First, the patient must have a clinically relevant scenario. That is, upon exposure to an antigen, the patient must have an appropriate allergic response, with the appropriate time interval, and clinical picture.
Second, the patient must demonstrate objective testing consistent with an allergic reaction. In other terms a mast cell is central to allergy. Mast cell distribution is known to be varied among organ systems, and the interaction of antigen with antigen-specific-IgE will cause mast cell degranulation, with the release of mediators, including, but not limited to, histamine, and heparin.
This process of antigen interaction with antigen-specific-IgE causes the major symptoms of allergy which vary by organ system.
In the upper airway, nasal, and sinus area, patients experience nasal and/or eye itching, nose and/or sinus congestion, rhinorrhea, post-nasal drip, sneezing, and/or itching. In the lower airway and lung area—patients experience shortness of breath, wheezing, chest tightness, and/or coughing.
In the skin, patients experience itching, redness, hives (i.e., urticaria), and/or swelling (i.e., angioedema).
In the cardiovascular system, patients experience hypotension, light-headedness, and/or syncope.
Allergic reactions can involve multiple organ systems and lead to any combination of the above symptoms. Alternatively, allergic reactions can also occur in an isolated organ system with symptoms limited to the specific organ system involved.
For making a diagnosis of an allergy, the first requirement is a scenario consistent with allergic disease. This is obtained through a thorough patient history.
The second component of an allergic diagnosis, objective testing for the allergy, is conventionally done via two methods. One method is an in vivo qualitative assay, and the other an in vitro quantitative assay. Both methods are unique and have their own merits and disadvantages. In addition, both methods test for the presence of specific-IgE-antibody. Antibody detection is required to make a definitive diagnosis of an allergy.
As previously mentioned, the first method of objective allergy testing is the in vivo qualitative method of specific-IgE detection. This method is allergy skin testing. Allergy skin testing involves the introduction of antigen into the skin to evaluate for mast cell activation. Mast cell activation is objectively observed in the skin as a wheal and flare reaction. The skin becomes raised and red (the wheal and flare), and this indicates the presence of allergen-specific-IgE. Controls are used during the test as well. A positive histamine control is used, and all patients should have a positive reaction to histamine. If a patient does not react to the control, the failure may be due to medications which blunt the effects of histamine (for example anti-histamines). A negative control of normal saline is used as well. The result from the saline should be negative, without reaction in all patients. However, it may be positive due to low mast cell stability or due to skin irritation. Both controls should be appropriate before the skin tests can be interpreted. This test is typically done on the forearm or the back. The results are visible at 20 to 30 minutes after antigen placement. The presence of antigen-specific-IgE does not make a definitive diagnosis of an allergy unless a clinical scenario consistent with an allergy is present.
On the other hand, RadioAllergoSorbent Test (RAST) testing is an in vitro quantitative method of specific-IgE detection. This is a laboratory based blood test which gives a quantitative measure of specific-IgE. Currently most in vitro quantitative allergy testing is done via an enzyme-linked immunosorbent assay (ELISA). The term “RAST testing” is used to refer to any method of quantitative in vitro specific-IgE antibody detection.
Both testing methods carry caveats and should be interpreted in the proper clinical light. In both testing methods, both the negative and positive controls must be adequate when interpreting skin test results.
In addition, the presence of specific-IgE does not mean that a patient is allergic to the allergen tested. For example, if a patient demonstrated the presence of Cat-specific-IgE on skin testing or RAST testing he is not necessarily allergic to cats. If in the presence of a cat he is symptom free—that is, he has no allergic symptoms—this patient is not allergic to cats. This is a “false positive” result which may be seen in all current testing methods. These “false positive” results indicate the importance of clinical interpretation of test results. That is for a definitive diagnosis of specific allergy to be made, the patient needs both positive testing as well as a history consistent with allergy.
In addition, the lack of detectable specific IgE does not definitively rule out an allergy. For example, a patient who has anaphylaxis, a life threatening allergic reaction to a honeybee sting, may have undetectable Honeybee-specific-IgE. This particular patient may be so sensitive to honeybee, that the undetectable level of IgE is enough to cause a life threatening reaction. Current testing methods are believed to have sensitivity and specificity which is 80%-95%, and clinical correlation is essential in determining a patient's allergic status.
There is a common assumption that specific IgE can be detected in the skin (in vivo) or blood (in vitro) regardless of the organ system (e.g., skin, gut, upper airway, lower airway, etc) which is affected by allergy. This assumption has been proven to be false. Lin et al., describes this in the following reference: Lin, X. P., et al., Local allergic reaction in food-hypersensitive adults despite a lack of systemic food-specific IgE. J Allergy Clin Immunol, 2002. 109(5): p. 879-87.
For example, five patients have five different allergic manifestations after eating a peanut. Patient 1 has isolated hives only. Patient 2 has isolated airway symptoms. Patient 3 has isolated hypotension, light-headedness and syncope. Patient 4 has only abdominal pain, and abdominal bloating. Patient 5 has all of the above symptoms. All of these five patients have allergic manifestations after eating a peanut, and all of them should avoid peanuts.
It is important to make a definitive diagnosis of an allergy, because the avoidance of the allergens can be very difficult. If skin or RAST testing for a specific-IgE is positive, this is an easy method to correlate to the history. In the case of positive testing and a strong history, a definitive diagnosis can be easily made. However, there are many patients in whom the specific-IgE cannot be detected via skin and RAST testing. This is especially true of patients with isolated gastrointestinal symptoms. Again, for a definitive diagnosis of allergy to be made: objective testing must be positive and the history must be consistent with allergy. The diagnosis of gastrointestinal allergy is difficult in patients with a mild to strong clinical history of allergy and negative skin and RAST testing. This is a problem because the negative skin and blood testing may not be truly reflective of the presence or lack thereof of antigen-specific-IgE within the gastrointestinal mucosa.
Gastrointestinal Allergy
There are many patients, with negative skin allergy testing and negative RAST testing, who feel their gastrointestinal symptoms are due to ingested antigens. It is difficult to make a diagnosis in these patients due to a lack of appropriate diagnostic modalities.
Patients with gastrointestinal allergy may have a wide variety of symptoms including, but not limited to: nausea, diarrhea, abdominal pain, flatulence, cramps, obstipation, constipation, and/or vomiting. Most patients are able to relate symptoms and worsening symptom severity to specific antigen intake. But without a diagnostic test a definitive diagnosis of allergy cannot be proven or ruled out. Patients may suggest multiple suspected allergic triggers for their gastrointestinal symptoms. However, a definitive diagnosis of gastrointestinal allergy must be made to avoid extreme lifestyle alterations which may include extreme efforts to avoid perceived allergy triggers.
The problem of diagnosing suspected isolated gastrointestinal allergy in patients with negative testing for antigen-specific-IgE is that objective testing is lacking for many patients. That is their clinical symptoms are mild to strongly suggestive of allergy, but their objective testing both via blood (RAST) and via skin testing is negative.
It has been shown that there can be organ specific, local production of specific allergic antibodies in such patients, and this can be a key factor in symptom creation. The current standard is to try to reproduce the gastrointestinal symptoms via a double blind placebo controlled food challenge (DBPCFC). But the DBPCFC is quite cumbersome, time consuming, and often non-reproducible. Consequently, it is not done by most physicians.
Colonoscopic Allergen Provocation (COLAP (1))
In 1997, COLAP was described in German literature, with the following citations: Bischoff, S. C., et al., Clinical significance of the colonoscopic allergen provocation test. Int Arch Allergy Immunol, 1997. 113(1-3): p. 348-51; and, Bischoff, S. C., et al., Colonoscopic allergen provocation (COLAP): a new diagnostic approach for gastrointestinal food allergy. Gut, 1997. 40(6): p. 745-53.
The Colonoscopic allergen provocation test (COLAP) is a specific allergy testing within the gastrointestinal tract. In the cecal portion of the colon, allergens are applied with a straight needle. The testing is very effective and clinically useful, especially in those patients who have a history consistent with allergic gastrointestinal disease, but with negative skin testing and RAST testing. This test as described by Bischoff does have many advantages, but there disadvantages as well. The literature does show the effectiveness of local gastrointestinal mucosal testing for isolated gastrointestinal symptoms thought to be related to allergy, but with negative objective skin testing and negative in vitro testing.
There are several positive aspects to local testing in the gastrointestinal mucosa. Specifically, 45% of antigens tested induced a positive reaction in the cecum, but not on the skin or via RAST. This type of testing can aid in gaining a definitive diagnosis in almost 77% of cases of suspected gastrointestinal allergy. In addition, results of the COLAP testing were visible within 20 minutes.
There are, however, several negative aspects of the COLAP testing described by Bischoff. The testing involved a colonoscopy and testing in the cecum of the colon. A straight needle was introduced via the endoscope into the cecum, and antigen was introduced. The mucosa of the cecum was then pricked (broken) via the needle, and the results were visually measured 20 minutes later. The technique itself is quite cumbersome and time consuming. The testing must be done one antigen at a time—antigen, by antigen, including controls. This prolongs the colonoscopy, and is often unacceptable depending on the number of antigens tested. Further, the cecum is a distant location, and a large amount antigen is used to fill the endoscope. This raises the cost of this type of testing. The most serious risk of COLAP testing involves a significant risk of gastrointestinal perforation. The mucosa of the cecum is the thinnest of the colon, and there is a significant risk of perforation, while using a straight needle to break or prick the mucosa. This is especially true because patients are not sedated for this procedure. They are under conscious sedation, and are still able to move. Movement increases the likelihood of perforation with a straight needle. The needle is also reused for each antigen, and flushed out in between uses. There is a risk of cross-contamination from previous antigens, which may cause false positive test results.
Because of the risk, cost, and cumbersome nature of this testing, it is not currently done anywhere on humans. Also it is not consistently reproducible because the amount of antigen used varies and the depth of penetration of the needle into the colonic mucosa varies. In sum, because of the negative aspects of the technique, colonoscopic allergen provocation is not done.